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DNA base excision repair (BER)

This research group, lead by Professor Svein Bjelland, studies DNA base excision repair (BER).

The main research interest is DNA base excision repair (BER). Focus is mainly on the initiating enzyme, that is different DNA glycosylases, of this repair pathway. 

 

It includes substrate specificities, catalytic mechanisms and influence on mutagenesis. Since the researchers are interested in base lesions caused by all three major chemical threats in cells, hydrolysis, reactive oxygen species (ROS) and methylation, they work with uracil-DNA glycosylase (UDG), glycosylases removing oxidized bases as well as methylpurine-DNA glycosylase, respectively.

Professor Bjelland's group plans to develop research in BER directly connected to epigenetics and cancer. 

 

Hydrolytic reactions

Since all cells are dependent on water, hydrolytic reactions challenge the chemical integrity of their DNA. Hydrolytic deamination of cytosine to uracil is one such important DNA damaging event causing C to T mutations if not repaired by BER prior to replication, initiated by UDG.

UDG is believed being mono-functional; only exhibiting activity for removal of the damaged base (uracil) from DNA. We have made the interesting discovery that human UDG (hUNG) also is able to incise uracil-DNA at the uracil site.

Thus, UDG can execute not only the first uracil excision step in BER but also a second incision step, leaving behind a 3´-α,β-unsaturated aldehyde and a 5´-phosphate. Our aim is to gain more insight in the in vivo consequences of this novel function. 

AlkA-stimulated mutagenesis

When ROS, generated as a by-product during aerobic respiration, oxidizes the 5-methyl group of thymine in DNA, 5-formyluracil (fU) forms in significant yields. Since fU pairs with other bases than A, it is mutagenic and needs to be repaired before replication. Several DNA glycosylases including the bacterial AlkA protein remove fU from DNA in vitro.

We recently verified this in vivo by showing an altered distribution of base substitutions induced by 5-formyldeoxyuridine (fdU) in alkA– compared to wild-type cells.

In addition to confirming the anticipated role of AlkA in alleviating mutation induction, we showed that the presence of AlkA also stimulated mutagenesis. Extrapolated to the mammalian system it means that DNA repair genes, under certain circumstances, may function as “oncogenes” rather than “tumour suppressor” or caretaker genes. 

We have investigated BER using Bacteria and thermophilic/hyperthermophilic Archaea as model systems. Recent years we have oriented our focus more towards the mammalian and particularly the human system. 

Publications (last 10 years):

Knævelsrud I, Kazazic S, Birkeland N-K & Bjelland S* (2014) The pH optimum of native uracil-DNA glycosylase of Archaeoglobus fulgidus compared to recombinant enzyme indicates adaption to cytosolic pH. Acta Biochim. Pol. 61, 393?395. 

Moen MN, Knævelsrud I, Haugland GT, Grøsvik K, Birkeland N-K, Klungland A & Bjelland S* (2011) Uracil-DNA glycosylase of Thermoplasma acidophilum directs long-patch base excision repair, which is promoted by deoxynucleoside triphosphates and ATP/ADP, into short-patch repair. J. Bacteriol. 193, 4495-4508.

Knævelsrud I, Moen MN, Grøsvik K, Haugland GT, Birkeland N-K, Klungland A, Leiros I & Bjelland S* (2010) The hyperthermophilic euryarchaeon Archaeoglobus fulgidus repairs uracil by single nucleotide replacement. J. Bacteriol. 192, 5755-5766. 

Knævelsrud I, Slupphaug G, Leiros I, Matsuda A, Ruoff P & Bjelland S* (2009) Opposite-base dependent excision of 5-formyluracil from DNA by hSMUG1. Int. J. Radiat. Biol. 85, 413-420. 

Ringvoll J, Moen MN, Nordstrand LM, Meira LB, Pang B, Bekkelund A, Dedon PC, Bjelland S, Samson LD, Falnes PØ & Klungland A (2008) AlkB homolog 2 (ABH2) mediated repair of ethenoadenine lesions in mammalian DNA. Cancer Res. 68, 4142-4149. 

Leiros I, Nabong MP, Grøsvik K, Ringvoll J, Haugland GT, Uldal L, Reite K, Olsbu IK, Knævelsrud I, Moe E, Andersen OA, Birkeland N-K, Ruoff P, Klungland A & Bjelland S* (2007) Structural basis for enzymatic excision of N1-methyladenine and N3-methylcytosine from DNA. EMBO J. 26, 2206-2217. 

Klungland A & Bjelland S (2007) Oxidative damage to purines in DNA: Role of mammalian Ogg1. DNA Repair 6, 481?488 (Review). 

*, corresponding author

 

The Bjelland research group:

  • Bjelland, Svein 
  • Alexeeva, Marina 
  • Tesfahun, Almaz 
  • Xu, Xiang Ming 

National collaborators: 

  • Professor Arne Klungland, University of Oslo, National Hospital 
  • Assistant Professor Ingar Leiros, University of Tromsø 

International collaborator:

  • Dr. Finn Kirpekar, University of Southern Denmark 
Illustration of DNA base repair

Illustration of DNA base repair (from Izaskun Muruzábal-Lecumberri's PhD thesis)